TNF-alpha and IL-1beta-mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells.


BACKGROUND:Tubulointerstitial fibrosis is a morphologic hallmark of chronic kidney disease and is a key factor in the prediction of progression to end-stage renal failure. Disruption of tubular basement membrane and interstitial extracellular matrix (ECM) via cytokine-induced alterations in matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) may be an important mechanism in this process. The presence of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and their effects on proximal tubular cells may be critical in this process. METHODS:Human proximal tubular cells were cultured in hormonally defined medium. Cells at 80% confluency were exposed to TNF-alpha (0.1 to 100 ng/mL) or IL-1beta (0.1 to 100 ng/mL) or a combination of both for 48 hours. Activity and expression of MMP-9 was examined by gelatin zymography and Western blot analysis. TIMP-1 expression was analyzed by Western blotting. Signaling through cytokine receptors, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways was investigated. RESULTS:TNF-alpha but not IL-1beta resulted in a dose-dependent increase in the latent form of MMP-9. TIMP-1 was decreased by treatment with either TNF-alpha or IL-1beta. Cotreatment with IL-1beta abolished the induction of MMP-9 but augmented the inhibition of TIMP-1 in the presence of TNF-alpha. Inhibition of PKC provided evidence of the importance of this pathway in mediating the cytokine-induced suppression of TIMP-1 in human kidney (HK-2) cells. Activation of the extracellular signal-regulated protein kinase (ERK1/2) MAPK mediated the up-regulation of MMP-9 by TNF-alpha whereas p38 was found to be involved in the IL-1beta-mediated inhibition of TNF-alpha-stimulated MMP-9. CONCLUSION:The differential effects of TNF-alpha and IL-1beta on proximal tubular MMP-9 and TIMP-1 expression are mediated through the TNF-RI, the IL-1-RI and the different signaling pathways of PKC, ERK1/2, and p38 MAPK. These findings may provide new insights into the role of proinflammatory cytokines TNF-alpha and IL-1beta in the development and possible therapeutic intervention in tubulointerstitial fibrosis.


Kidney Int


Kidney international


Nee LE,McMorrow T,Campbell E,Slattery C,Ryan MP




Has Abstract


2004-10-01 00:00:00














  • Patient education and access of ESRD patients to renal replacement therapies beyond in-center hemodialysis.

    abstract:BACKGROUND:Nephrologists report that patients' choice should play an important role in the selection of renal replacement therapy (RRT) for end-stage renal disease (ESRD). In the United States, kidney transplant rates remain low and <10% of patients utilize home dialysis therapies. This study examined the effect of pre...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Mehrotra R,Marsh D,Vonesh E,Peters V,Nissenson A

    更新日期:2005-07-01 00:00:00

  • Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis.

    abstract:BACKGROUND:Microarray technology is a powerful tool that can probe the molecular pathogenesis of renal injury. In this present study microarray analysis was used to monitor serial changes in the renal transcriptome of a rat model of mesangial proliferative glomerulonephritis. Administration of anti-Thy1 antibody result...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Sadlier DM,Ouyang X,McMahon B,Mu W,Ohashi R,Rodgers K,Murray D,Nakagawa T,Godson C,Doran P,Brady HR,Johnson RJ

    更新日期:2005-12-01 00:00:00

  • Nonsteroidal anti-inflammatory drug use is associated with cancer risk reduction in chronic dialysis patients.

    abstract::Previous studies have shown that nonsteroidal anti-inflammatory drug (NSAID) use might be associated with a lower risk of developing cancer in the general population. Patients on dialysis have increased risk for cancer, but there are no studies to determine the relationship between NSAID use and cancer risk in these p...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Ou SM,Chen YT,Chao PW,Lee YJ,Liu CJ,Yeh CM,Chen TJ,Chen TW,Yang WC,Li SY

    更新日期:2013-07-01 00:00:00

  • Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis.

    abstract::Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated b...

    journal_title:Kidney international

    pub_type: 杂志文章,评审


    authors: Thakker RV

    更新日期:2000-03-01 00:00:00

  • Chronic peritoneal dialysis in iron-deficient rats with solutions containing iron dextran.

    abstract:BACKGROUND:We evaluated the effects of different concentrations of iron dextran administered through the intraperitoneal route, in iron-deficient rats, on hematocrit (Hct in percentage), serum iron (mg/dL), total iron binding capacity (TIBC in mg/dL), and the function and histology of the peritoneal membrane. METHODS:...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Reddy DK,Moore HL,Lee JH,Saran R,Nolph KD,Khanna R,Twardowski ZJ

    更新日期:2001-02-01 00:00:00

  • Higher net acid excretion is associated with a lower risk of kidney disease progression in patients with diabetes.

    abstract::Higher diet-dependent nonvolatile acid load is associated with faster chronic kidney disease (CKD) progression, but most studies have used estimated acid load or measured only components of the gold standard, net acid excretion (NAE). Here we measured NAE as the sum of urine ammonium and titratable acidity in 24-hour ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Scialla JJ,Asplin J,Dobre M,Chang AR,Lash J,Hsu CY,Kallem RR,Hamm LL,Feldman HI,Chen J,Appel LJ,Anderson CA,Wolf M,Chronic Renal Insufficiency Cohort Study Investigators.

    更新日期:2017-01-01 00:00:00

  • Flying podocytes.

    abstract::Recent insights have defined the central role of podocytes both in rare genetic diseases and as a general determinant of the progression of human glomerular diseases. In a recent issue of Nature, Weavers et al. described a podocyte-like cell type in Drosophila, the nephrocyte, that closely resembles mammalian podocyte...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Simons M,Huber TB

    更新日期:2009-03-01 00:00:00

  • Role of vascular endothelial growth factor in the regulation of angiogenesis.

    abstract::Compelling evidence indicates that vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. The loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF plays also a critical role in kidney development, and its inactivation d...

    journal_title:Kidney international

    pub_type: 杂志文章,评审


    authors: Ferrara N

    更新日期:1999-09-01 00:00:00

  • Changes in anemia management and hemoglobin levels following revision of a bundling policy to incorporate recombinant human erythropoietin.

    abstract::In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Hasegawa T,Bragg-Gresham JL,Pisoni RL,Robinson BM,Fukuhara S,Akiba T,Saito A,Kurokawa K,Akizawa T

    更新日期:2011-02-01 00:00:00

  • Peripheral donor leukocytes prolong survival of rat renal allografts.

    abstract:BACKGROUND:The development of strategies to enhance the survival of transplanted organs and to potentially lower or even discontinue immunosuppressive therapy would represent a significant advancement in post-transplant patient care. METHODS:We studied the effect of pretransplant infusion of donor leukocytes alone or ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Noris M,Azzollini N,Mister M,Pezzotta A,Piccinini G,Casiraghi F,Cugini D,Perico N,Orisio S,Remuzzi G

    更新日期:1999-09-01 00:00:00

  • Production of hyaluronan by glomerular mesangial cells in response to fibronectin and platelet-derived growth factor.

    abstract::The formation of the non-sulphated glycosaminoglycan hyaluronan by cells of the renal glomerulus in diabetes may contribute to altered matrix composition. We describe an increased production of hyaluronan from mesangial cell-enriched glomerular cores from diabetic animals, and further show that increased hyaluronan pr...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Dunlop ME,Clark S,Mahadevan P,Muggli E,Larkins RG

    更新日期:1996-07-01 00:00:00

  • Renal iron handling in the nephrotic syndrome.

    abstract::Renal iron handling was characterized in three experimental models of the nephrotic syndrome: puromycin aminonucleoside, adriamycin and nephrotoxic serum. In adriamycin-induced nephrotic syndrome, which has previously been shown to result from alterations in pore size of the filtration barrier, the transferrin leak wa...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Alfrey AC,Hammond WS

    更新日期:1990-06-01 00:00:00

  • Recombinant human growth hormone exacerbates chronic puromycin aminonucleoside nephropathy in rats.

    abstract::Growth failure is a cardinal feature of chronic renal failure in children. Administration of recombinant human growth hormone (rhGH) ameliorates this problem but may adversely affect the kidney and hasten the progression to end-stage renal disease. We conducted experiments to examine the impact of rhGH on the severity...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Trachtman H,Futterweit S,Schwob N,Maesaka J,Valderrama E

    更新日期:1993-12-01 00:00:00

  • Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis.

    abstract::Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Petersen M,Thorikay M,Deckers M,van Dinther M,Grygielko ET,Gellibert F,de Gouville AC,Huet S,ten Dijke P,Laping NJ

    更新日期:2008-03-01 00:00:00

  • Identification of a single base insertion in the COL4A5 gene in Alport syndrome.

    abstract::We identified a novel mutation in the COL4A5 gene of a Japanese patient with Alport syndrome. A combination of in vitro amplification of the exons with single strand conformation polymorphisms (SSCP) analysis suggested the presence of a mutation in exon 48. Sequencing of the amplified DNA revealed a single base (T) in...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Nakazato H,Hattori S,Matsuura T,Koitabashi Y,Endo F,Matsuda I

    更新日期:1993-11-01 00:00:00

  • Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus.

    abstract::Nephropathia epidemica (NE) caused by Puumala hantavirus is one type of hemorrhagic fever with renal syndrome (HFRS). There is considerable variability in the clinical severity of NE. Many infections are subclinical but the disease can even be fatal. We questioned whether the wide spectrum in the outcome of NE is depe...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Mustonen J,Partanen J,Kanerva M,Pietilä K,Vapalahti O,Pasternack A,Vaheri A

    更新日期:1996-01-01 00:00:00

  • Microalbuminuria three years after recovery from Escherichia coli O157 hemolytic uremic syndrome due to municipal water contamination.

    abstract:BACKGROUND:Knowledge of the long-term renal prognosis of diarrhea associated hemolytic uremic syndrome (HUS) is important for patient counseling and follow-up. However, estimates of long-term risk are highly variable, with previous studies not using a healthy control group. METHODS:A municipal water system in the smal...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Garg AX,Clark WF,Salvadori M,Macnab J,Suri RS,Haynes RB,Matsell D,Walkerton Health Study Investigators.

    更新日期:2005-04-01 00:00:00

  • A strategy for in vitro propagation of rat nephrons.

    abstract:BACKGROUND:Recent advances in the understanding of the molecular biology of rodent renal development have lead to the ability to culture the components of the developing rat kidney-the ureteric bud (UB) and the metanephric mesenchyme (MM)-in isolation from one another. Here we here describe a method for subculturing an...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Steer DL,Bush KT,Meyer TN,Schwesinger C,Nigam SK

    更新日期:2002-12-01 00:00:00

  • Importance of angiogenic action of angiotensin II in the glomerular growth of maturing kidneys.

    abstract::We studied the effect of three antihypertensive drugs on the growth of glomeruli in four- to five-week-old Munich-Wistar rats (N = 24), which were undergoing rapid maturation processes. Young rats were given an angiotensin converting enzyme inhibitor (ACEI, enalapril, 50 mg/liter drinking water), verapamil (50 mg/lite...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Fogo A,Yoshida Y,Yared A,Ichikawa I

    更新日期:1990-12-01 00:00:00

  • Effects of oxygen breathing and erythropoietin on hypoxic vasodilation in uremic anemia.

    abstract::Loss of hypoxic vasodilation has been proposed as a causative factor in the development of hypertension in dialysis patients treated with recombinant human erythropoietin (rHuEPO). Venous occlusion plethysmography was therefore performed on 22 dialysis patients (aged 23 to 71 years, dialysis duration 6 to 260 months, ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Roger SD,Grasty MS,Baker LR,Raine AE

    更新日期:1992-10-01 00:00:00

  • Prospective assessment of antidonor cellular alloreactivity is a tool for guidance of immunosuppression in kidney transplantation.

    abstract::Current characterization of the immune risk in renal transplant patients is only focused on the assessment of preformed circulating alloantibodies; however, alloreactive memory T cells are key players in mediating allograft rejection. Immune monitoring of antidonor alloreactive memory/effector T cells using an IFN-γ E...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Bestard O,Cruzado JM,Lucia M,Crespo E,Casis L,Sawitzki B,Vogt K,Cantarell C,Torras J,Melilli E,Mast R,Martinez-Castelao A,Gomà M,Reinke P,Volk HD,Grinyó JM

    更新日期:2013-12-01 00:00:00

  • Tetrahydrobiopterin is a limiting factor of nitric oxide generation in interleukin 1 beta-stimulated rat glomerular mesangial cells.

    abstract::Treatment of mesangial cells with recombinant human interleukin 1 beta (IL-1 beta) triggers the expression of a macrophage-type of nitric oxide (NO) synthase and the subsequent increase of cellular concentration of cGMP and nitrite production. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthase, and in ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Mühl H,Pfeilschifter J

    更新日期:1994-11-01 00:00:00

  • Gentamicin pharmacokinetics during slow daily home hemodialysis.

    abstract:BACKGROUND:Gentamicin is commonly used in hemodialysis patients. Gentamicin pharmacokinetics during traditional hemodialysis have been described. Slow daily home (SDH) hemodialysis (7 to 9 hours a day/6 days a week) use is increasing due to benefits observed with increased hemodialysis. We determined gentamicin pharmac...

    journal_title:Kidney international

    pub_type: 临床试验,杂志文章


    authors: Manley HJ,Bailie GR,McClaran ML,Bender WL

    更新日期:2003-03-01 00:00:00

  • Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group.

    abstract:UNLABELLED:Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. BACKGROUND:In the management of patients with mild secondary hyperparathyroidism, it is not known whether calcium supplementation alone is sufficient to correct abnormalities in bone and mineral metabolism or if calcit...

    journal_title:Kidney international

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Indridason OS,Quarles LD

    更新日期:2000-01-01 00:00:00

  • Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression in Autosomal Dominant Polycystic Kidney Disease.

    abstract::Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Identification of an early biomarker that can predict progression of CKD is urgently needed. In an earlier Consortium for Radiolog...

    journal_title:Kidney international

    pub_type: 杂志文章,多中心研究


    authors: Yu ASL,Shen C,Landsittel DP,Harris PC,Torres VE,Mrug M,Bae KT,Grantham JJ,Rahbari-Oskoui FF,Flessner MF,Bennett WM,Chapman AB,Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP).

    更新日期:2018-03-01 00:00:00

  • Hyperuricemia induces endothelial dysfunction.

    abstract:BACKGROUND:Hyperuricemia has been linked to cardiovascular and renal diseases, possibly through the generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction. The enzymatic effect of xanthine oxidase is the production of ROS and uric acid. Studies have shown that inhibiting xanthine oxidase wit...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Khosla UM,Zharikov S,Finch JL,Nakagawa T,Roncal C,Mu W,Krotova K,Block ER,Prabhakar S,Johnson RJ

    更新日期:2005-05-01 00:00:00

  • Tamm-Horsfall glycoprotein binds IgG with high affinity.

    abstract::Tamm-Horsfall protein (THP), a monomeric glycoprotein (M(r) 80 to 100 kDa), is produced by the mammalian kidney's thick ascending limb of Henle cells and excreted into the urine. The function of THP is uncertain. Here we report that a high molecular weight contaminant in sheep THP (sTHP) preparations was identified as...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: Rhodes DC,Hinsman EJ,Rhodes JA

    更新日期:1993-11-01 00:00:00

  • Assessing dialysis adequacy and dietary intake in the individual hemodialysis patient.

    abstract:BACKGROUND:Urea kinetic modeling (UKM) and food records are widely used to assess the dialysis adequacy. Clinicians use these methods in individual patients to decide whether the dialysis prescription should be adjusted. We determined the variation in UKM parameters and dietary intake within individual patients in orde...

    journal_title:Kidney international

    pub_type: 临床试验,杂志文章,多中心研究


    authors: Kloppenburg WD,Stegeman CA,Hooyschuur M,van der Ven J,de Jong PE,Huisman RM

    更新日期:1999-05-01 00:00:00

  • A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss.

    abstract::Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the ...

    journal_title:Kidney international

    pub_type: 杂志文章


    authors: de Kok MJ,Schaapherder AF,Mensink JW,de Vries AP,Reinders ME,Konijn C,Bemelman FJ,van de Wetering J,van Zuilen AD,Christiaans MH,Baas MC,Nurmohamed AS,Berger SP,Ploeg RJ,Alwayn IP,Lindeman JH

    更新日期:2020-06-01 00:00:00

  • Rebound kinetics of beta2-microglobulin after hemodialysis.

    abstract:BACKGROUND:Evaluation of beta2-microglobulin (beta2m) removal during hemodialysis using predialysis and immediate postdialysis plasma concentrations is only valid in the absence of postdialysis rebound. Postdialysis rebound of beta2m has not been studied extensively, and its importance in the determination of beta2m cl...

    journal_title:Kidney international

    pub_type: 临床试验,杂志文章


    authors: Leypoldt JK,Cheung AK,Deeter RB

    更新日期:1999-10-01 00:00:00